Exogenous NADPH increases cerebral blood flow through NADPH oxidase-dependent and -independent mechanisms.

OBJECTIVE

NADPH, a substrate for the superoxide-producing enzyme NADPH oxidase, produces vasodilation in the cerebral circulation. However, the mechanisms of the effect have not been fully elucidated. We used a peptide inhibitor of NADPH oxidase (gp91ds-tat) and null mice lacking the gp91phox subunit of NADPH oxidase to examine the mechanisms of the cerebrovascular effects of exogenous NADPH.

METHODS AND RESULTS

Cerebral blood flow (CBF) was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. Superfusion with NADPH increased CBF (27% at 100 micromol/L) without affecting the EEG. The CBF increase was attenuated by the free-radical scavenger MnTBAP (-54%, P<0.05) but not by the H2O2 scavenger catalase. The response was also attenuated by gp91ds-tat (-64%, P<0.05) and by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (-44%, P<0.05). The increase in CBF produced by NADPH was attenuated in gp91-null mice (-41%, P<0.05). NADPH increased production of reactive oxygen species, assessed by hydroethidine microfluorography, an effect blocked by MnTBAP or gp91ds-tat and not observed in gp91-null mice.

CONCLUSIONS

These data suggest that the mechanisms of the CBF increases produced by exogenous NADPH are multifactorial and include NADPH oxidase-dependent and -independent factors.